Combined association and linkage analysis applied to the APOE locus

Combined association and linkage analysis is a powerful tool for pinpointing functional quantitative traits (QTLs) responsible for regions of significant linkage identified in genome‐wide scans. We applied this technique to apoE plasma levels and the APOEε2/ε3/ε4 polymorphism in two Dutch twin cohorts of different age ranges. Across chromosome 19, short tandem repeats and the APOEε2/ε3/ε4 polymorphism were genotyped in adolescent (aged 13–22 years) and adult (aged 34–62 years) Dutch twins. In both samples, evidence for indicative linkage with plasma apoE levels was found (maximum LOD score (MLS)=0.8, MLS=2.5, respectively) at 19q13.32. These linkage regions included the APOE locus. As expected, the APOEε2/ε3/ε4 polymorphism was strongly associated with apoE plasma levels in both samples. An extension of the between/within families association test developed by Fulker et al. ([1999] Am. J. Hum. Genet. 64:259–267) showed that these associations were not due to population stratification. The combined association and linkage analyses revealed that the association of the APOEε2/ε3/ε4 polymorphism with apoE plasma levels completely explained the linkage in the adolescent twins and partly in the adult twins. © 2004 Wiley‐Liss, Inc.